The control of energy metabolism within intact tissues is being investigated using a variety of techniques and tissues. The relation between the rates of energy conversion, via mitochondrial oxidative phosphorylation and glycolysis, and work output is being determined in the heart in vivo under controlled conditions. In addition, studies on the isolated perfused heart, isolated mitochondria and cultured cells are also being used to compliment the in vivo studies., In all of these preparations a tight coupling between the rate of work and the rate of energy conversion has been observed. In order to gain insight into the mechanism of this coupling, several of the key metabolic intermediates are also being determined as a function of work output using non-invasive techniques. Adenosine di-and tri- phosphates, inorganic phosphate, creatine phosphate pH and the steady state turnover of these compounds are being monitored using 31P NMR. In vivo mitochondrial redox state and oxygenation is being monitored using optical spectroscopy. Classical models concering the control of energy conversion with in cells involve the intracellular concentrations of adenosine di and tri-phosphates as well as inorganic phosphate. However, in our in vivo and perfused heart studies we have demonstrated that these compounds are not the major determinants of the rate of energy conversion. Further, in both the isolated perfused heart and mitochondria studies we have demonstrated that the redox state of NADH can control the rate of mitochondrial respiration and that the NAD redox state does change appropriately (i.e. becomes more reduced) when the isolated perfused heart is stimulated to more work. These data suggest that the control of energy conversion of the heart is actually controlled at the level of substrate oxidation most likely involving the regulation of substrate dehydrogenase activity.